1,4-Difluoro-2,5-dimethoxybenzene as a precursor for iterative double benzyne-furan Diels-Alder reactions

Article abstract of DOI:10.1021/jo050112e

(Chemical Equation Presented) The use of 1,4-difluoro-2,5-dimethoxybenzene as a novel precursor for iterative two-directional benzyne-furan Diels-Alder reactions, using a range of 2- and 3-substituted furans, is reported. Substituted oxabenzonorbornadiene

Full text of DOI:10.1021/jo050112e

1,4-Difluoro-2,5-dimethoxybenzene as a Precursor for Iterative
Double Benzyne-Furan Diels-Alder Reactions
Gillian E. Morton and Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, England
agmb@imperial.ac.uk
Received January 19, 2005
The use of 1,4-difluoro-2,5-dimethoxybenzene as a novel precursor for iterative two-directional
benzyne-furan Diels-Alder reactions, using a range of 2- and 3-substituted furans, is reported.
Substituted oxabenzonorbornadienes were synthesized following the initial Diels-Alder reaction,
which upon ring opening under acidic conditions gave substituted naphthol derivatives. Highly
substituted anthracenols were generated in the second benzyne-furan Diels-Alder reaction
following acid-catalyzed isomerization of the cycloadducts.
Introduction
As part of our ongoing interest in diverse biologically
active benz[a]anthracene antibiotics,1 we sought to ex-
plore the use of derivatives of the double benzyne
cyclohexa-1,2,3-trien-5-yne (1)2,3 for the elaboration of
polyfunctional anthraquinone derivatives from simple
arene precursors (Figure 1). Hart has previously reported
the double benzyne cycloaddition reactions of the diamine
24 by lead tetraacetate oxidation in the presence of
furans. In addition, he has prepared double furan,
pyrrole, and cyclopentadiene cycloadducts from the tetra-
bromides 4 using lithium-bromine exchange and elimi-
nation of lithium bromide to generate intermediates
equivalent to the double benzyne 3.5-8 With careful
control of the butyllithium stoichiometry and with some
substrates, Hart was able to prepare unsymmetrical
double cycloadducts such as the pentacycle 5. However,
in many cases the greater solubility of the initial mono-
cycloadduct, such as 6 at low temperature, relative to the
starting tetrabromide 4, was a problem for the efficient
preparation of unsymmetrical double cycloadducts. Al-
(1) Thomson, R. H. Naturally Occurring Quinones III; Chapman and
Hall: New York, 1987.
(2) Sato, T.; Arulmozhiraja, S.; Niino, H.; Sasaki, S.; Matsuura, T.;
Yabe, A. J. Am. Chem. Soc. 2002, 124, 4512.
(3) Moriyama, M.; Yabe, A. Chem. Lett. 1998, 27, 337.
(4) Hart, H.; Ok, D. J. Org. Chem. 1986, 51, 979.
(5) Hart, H.; Raju, N.; Meador, M. A.; Ward, D. L. J. Org. Chem.
1983, 48, 4357.
FIGURE 1. Two-directional benzyne-furan Diels-Alder
reactions: compounds, intermediates, and products.
though the formation of 6 (R1 ) R2 ) OMe) was found to
proceed in only modest yields (65%), the corresponding
butyl and hexyl ethers 6 (R1 ) R2 ) OBu or OC6H13) could
be produced in better yields.9-12 Recently, Lee and co-
(6) Hart, H.; Nwokogu, G. C. Tetrahedron Lett. 1983, 24, 5721.
(7) Hart, H.; Lai, C. Y.; Nwokogu, G. C.; Shamouilian, S. Tetrahe-
dron 1987, 43, 5203.
(8) Hart, H.; Bashir-Hashemi, A.; Luo, J.; Meador, M. A. Tetrahe-
dron 1986, 42, 1641.
10.1021/jo050112e CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/29/2005
J. Org. Chem. 2005, 70, 3525-3529
3525

Morton and Barrett
SCHEME 1. Conversion of Difluoride 8 into
workers reported the use of benzobisoxadisiloles as
synthetic equivalents for cyclohexa-1,2,3-trien-5-yne (1).13
We considered that it should be possible to extend the
Hart methodology with the use of double benzyne precur-
sors of lower molecular weight than tetrabromides and
we sought to examine 2,5-difluoro-1,4-dimethoxybenzene
8 as a precursor for the hypothetical intermediate 7 and
its use in sequential double Diels-Alder reactions with
two different furans. There is indirect precedent to
support the expectation that difluoride 8 should be a
useful reagent. 3-Fluoroanisole has been reported to
undergo C-2 lithiation at -78 °C and the carbanion
trapped with a range of electrophiles or transformed into
fluorinated biphenyl derivatives via elimination on warm-
ing to produce the benzyne intermediate.14-17 On the
basis of known related transformations,18,19 it is reason-
able to speculate that benzyne 9 may undergo cycload-
dition reactions regioselectively with monosubstituted
furan derivatives.
Cycloadducts by Lithiation and Intermediacy of
Benzyne 9a
Results and Discussions
Sequential addition of n-butyllithium (1 equiv) and
furan 10a to difluoride 8 in THF at -78 °C and warming
up to 0 °C gave the cycloadduct 11a (80%) yield. This
product was subsequently aromatized, by treatment with
6 M hydrochloric acid, to provide the naphthol 13a as
the only product (86%). The initial benzyne 9 cycloaddi-
tion reaction was extended to a range of 2- and 3-sub-
stituted furans 10b-e and 14a,b to provide the adducts
11b-e and 15a,b respectively (45-76%) (Scheme 1,
Table 1). The adducts 11b-e were rearranged under
acidic conditions to produce mixtures of naphthols 12 and
13 (1:1 to 1:0). In the same way, the adducts 15a and
15b were aromatized to produce naphthols 16, 17, and
18 (1:1:0 and 1:2:1, respectively). Attempted cycloaddition
with 3-phenylfuran 14c20 was unsuccessful and only gave
intractable mixtures consistent with the findings by Batt
with this dienophile.21 In most cases the isomeric naph-
thol derivatives were easily separated by chromatography
and fully characterized. However, the naphthols 16b,
17b, and 18b, derived from 3-benzylfuran21 (14b) (entry
7), were only partially separable and 16b and 18b were
characterized as a mixture. Assignments of the structures
of the naphthols 12, 13, and 16-18 were carried out by
X-ray crystallography (13a and 17a) or NoESY NMR
spectroscopy (see the Supporting Information).
a Reagents and conditions: (a) 8, BuLi, THF, -78 to 0 °C; (b)
HCl, H2O, MeOH, ∆.
TABLE 1. Preparation of Benzyne-Furan Cycloadducts
from Difluoride 8
isomer
entry furan cycloadduct (%)
naphthols (%)
13a (86)
12b + 13b (79)
12c + 13c (80)
12d + 13d (90)
12e (68)
ratioa
1
2
3
4
5
6
7
10a
10b
10c
10d
10e
14a
14b
11a (80)
11b (76)
c
0:1b
1:1b
1:1d
5:1b
1:0b
1:1b
1:2:1e
c
11e (64)
15a (45)
15b (56)
(9) Choi, M. T. M.; Yang, Q.; Mak, T. C. W.; Ng, D. K. P. J. Chem.
Res., Synop. 2002, 644.
(10) Meier, H.; Rose, B.; Schollmeyer, D. Liebigs Ann./Recl. 1997,
1173.
(11) Meier, H.; Rose, B. Liebigs Ann./Recl. 1997, 663.
(12) Rack, M.; Hauschel, B.; Hanack, M. Chem. Ber. 1996, 129, 237.
(13) Chen, Y.-L.; Sun, J.-Q.; Wei, X.; Wong, W.-W.; Lee, A. W. M. J.
Org. Chem. 2004, 69, 7190.
(14) Adejare, A.; Miller, D. D. Tetrahedron Lett. 1984, 25, 5597.
(15) Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E.
Tetrahedron Lett. 1992, 33, 7499.
(16) Katsoulos, G.; Takagishi, S.; Schlosser, M. Synth. Lett. 1991,
10, 731.
16a + 17a (79)
16b, 17b + 18b (82)
a Isomer ratio refers to 12:13 for entries 1-5, 16a:17a for entry
6, and 16b:17b:18b for entry 7. b Isomers separated and fully
characterized. c Intermediate cycloadducts not isolated but con-
verted directly into naphthols. d Isomers inseparable and charac-
terized as a mixture. e Isomers partially separable, 17b charac-
terized as a single isomer and 16b/18b characterized as a mixture.
To carry out the second benzyne-furan Diels-Alder
reaction, protection of the free phenol was required.
O-Methylation of phenol 13a, lithiation, benzyne forma-
tion, and trapping with furan 10a gave the cycloadduct
21a (63%), which was aromatized under acidic conditions
to produce the anthracenols 22a and 23a (82%, 4:1). The
second benzyne-furan (10a) cycloaddition reaction was
(17) Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T.
J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972.
(18) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew.
Chem., Int. Ed. 2004, 43, 3935.
(19) Gribble, G. W.; Keavy, D. J.; Branz, S. E.; Kelly, W. J.; Pals,
M. A. Tetrahedron Lett. 1988, 29, 6227.
(20) Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47, 1590.
(21) Batt, D. G.; Jones, D. G.; La Greca, S. J. Org. Chem. 1991, 56,
6704.
3526 J. Org. Chem., Vol. 70, No. 9, 2005

Iterative Double Benzyne-Furan Diels-Alder Reactions
SCHEME 2. Second Benzyne-Furan Diels-Alder
Reactionsa
FIGURE 2. Naphthalene and anthracene derivatives pre-
pared with two-directional benzyne-furan Diels-Alder reac-
tions from difluoride 8.
of the acid-catalyzed ring opening of the cycloadduct 11a
was controlled by preferential formation of the more
stabilized carbenium ion 29 (Figure 3) on scission of the
bridgehead C-O bond. The influence of relative carben-
ium ion stability on the direction of opening of benzyne-
furan cycloadducts has previously been reported by Giles
and Sargent.22 In addition, it is important to note the
benzylic carbenium ion stabilizing effects of an aryl
fluorine substituent by resonance.23 The cycloadducts 11c
and 11d (Table 1, entries 3 and 4) were found to be
especially prone to isomerization to a naphthol on account
of the electron-donating R2 substituents. The regioselec-
tivities of the cycloadditions of 2-arylfurans 10d and 10e
with the benzyne 9 favoring formation of the isomers 12
over isomers 13, following acid-catalyzed isomerization,
are consistent with the known inductive polarization of
4-fluorobenzyne.24 Since the yield of the naphthol 12e
was only modest, it is possible that the apparent high
selectivity was the result of partial decomposition during
manipulation rather than regiospecific cycloaddition. The
lack of regioselectivity in the cycloadditions of benzyne
9 with furans 10b19,25 and 10c26-29 was surprising given
reports of their reactions with other benzynes. Finally,
the preference for formation of the 2-benzylnaphthols 16b
and 17b (Table 1, entry 7) presumably was the result of
phenonium ion30 30 participation during the acid-
catalyzed rearrangement. Furan 10a (Table 2) and
a Reagents and conditions: (a) MeI, NaH, DMF, 20 °C; (b) 10a,
BuLi, THF, -78 to 0 °C; (c) HCl, H2O, THF ∆.
TABLE 2. Preparation of Cycloadducts and
Anthracenols from Fluoronaphthalenes and Furan (10a)
fluoronaphthalene cycloadduct anthracenols isomer
entry
(%)
(%, ratio)
(%)
ratioa
1
2
3
4
5
6
7
20a (100)
19b(89)
20b (81)
19c (81)
19d (81)c
19e (94)
24 (85)
21a (63, -) 22a + 23a (82)b
21b (88, -) 22b + 23b (85)b
21b (86, -)
4:1
1:1
21c (61, -) 22c (83)
21d (70, -) 22d + 23d (71)b
21e (82, -) 22e + 23e (83)b
2:1
3:1
2:1
25 (74, -)
26a + 26b (78)b
a Isomer ratio refers to 22:23 for entries 1-6, 26a:26b for entry
7. b Isomers inseparable and characterized as a mixture. c Mixture
of isomers (19d:20d ) 5:1) obtained from mixture of isomers (12d:
13d ) 5:1).
extended to a range of fluorides 19, 20, and 24 to provide
the adducts 21 and 25 (61-88%) and the corresponding
anthracenols 22, 23, and 26 (71-85%) on acid-catalyzed
isomerization (Scheme 2, Table 2, Figure 2). In addition,
the reaction and aromatization was extended to 2-me-
thylfuran (10b) and 2-methoxyfuran (10c) to provide the
cycloadducts 27 and anthracenols 28 (Scheme 2, Table
3, Figure 2). In most cases, the isomeric mixtures of
anthracenol derivatives could not be separated by chro-
matography but were characterized as mixtures. Struc-
tures of the major isomers were characterized by NoESY
NMR spectroscopy (see the Supporting Information).
It is germane to comment briefly on the regioselectivi-
ties of the transformations in Tables 1-3. The direction
(22) Giles, R. G. F.; Hughes, A. B.; Sargent, M. V. J. Chem. Soc.,
Perkin Trans. 1 1991, 6, 1581.
(23) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1383.
(24) Roberts, J. D.; Vaughan, C. W.; Carlsmith, L. A.; Semenow, D.
A. J. Am. Chem. Soc. 1956, 78, 611.
(25) Giles, R. G. F.; Sargent, M. V.; Sianipar, H. J. Chem. Soc.,
Perkins 1 1991, 6, 1571.
(26) Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992,
114, 3568.
(27) Hosoya, T.; Takashiro, E.; Takashi, M.; Suzuki, K. J. Am. Chem.
Soc. 1994, 116, 1004.
J. Org. Chem, Vol. 70, No. 9, 2005 3527

Morton and Barrett
TABLE 3. Preparation of Cycloadducts and Anthracenols from Fluoronaphthalenes and 2-Methylfuran (10b) or
2-Methoxyfuran (10c)a
fluoronaph-
thalene (%)
cycloadducts
(%, ratio)
anthracenols
(%)
isomer
ratiob
entry
1
2
3
4
20a
19dc
20a
19c
27a and 27b (92, 1:2)
28a + 28b (61%)c
28f + 28g (87)c
28c + 28d (83)c
28e (84)
1:1
1:1
5:3
27c and 27d (70, 1:1)
d
d
a Furan 10b in entries 1 and 2, furan 10c in entries 3 and 4. b Isomer ratio refers to 28a:28b for entry 1, 28f:28g for entry 2, 28c:28d
for entry 3. c Isomers inseparable and characterized as a mixture. d Cycloadduct not isolated but directly aromatized. e Chromatographically
separated 28c and 28d characterized as a single isomers.
cm-1; 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.69 (dd, 1H,
J ) 1.0, 8.5 Hz), 7.31 (t, 1H, J ) 8.0 Hz), 6.96 (d, 1H, J ) 7.5
Hz), 6.56 (d, 1H, JH-F ) 13.5 Hz), 4.11 (d, 3H, JH-F ) 1.5 Hz),
3.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9 (d, JC-F
)
6.5 Hz), 152.6 (d, JC-F ) 10.5 Hz), 150.3 (d, JC-F ) 243.0 Hz),
134.7 (d, JC-F ) 12.0 Hz), 126.1, 124.6, 117.5 (d, JC-F ) 3.0
Hz), 113.3, 112.1, 96.0 (d, JC-F ) 26.5 Hz), 62.8 (d, JC-F ) 6.5
Hz), 55.9; MS (CI, NH3) m/z 223 (M + H)+; HRMS (CI) m/z
calcd for C12H12FO3 (M + H)+ 223.0771, found (M + H)+,
223.0769. Anal. Calcd for C12H11FO3: C, 64.86; H, 4.99.
Found: C, 64.94; H 4.82. Crystal data for 13a: C12H11FO3, M
) 222.21, monoclinic, P21/n (no. 14), a ) 16.500(6) Å, b )
3.962(3) Å, c ) 17.251(7) Å, â ) 113.076(13)°, V ) 1037.5(11)
Å3, Z ) 4, Dc ) 1.423 g cm-3, µ(Cu KR) ) 0.962 mm-1, T )
293 K, colorless needles; 1544 independent measured reflec-
tions, F2 refinement, R1 ) 0.066, wR2 ) 0.190, 974 independent
observed absorption-corrected reflections [|Fo| > 4σ(|Fo|), 2θmax
) 120°], 150 parameters; CCDC 261199.
2-Fluoro-1,4,8-trimethoxynaphthalene (20a). NaH (60%
dispersion in mineral oil; 23 mg, 0.56 mmol, 1.24 equiv)
followed by MeI (79 mg, 0.56 mmol, 1.24 equiv) were added to
naphthol 13a (100 mg, 0.45 mmol) in dry DMF (1 mL) and
the mixture was stirred for 18 h at 20 °C. H2O was added to
quench the reaction and the mixture extracted with EtOAc (2
× 25 mL), dried (Na2SO4), rotary evaporated, and chromato-
graphed (1:1 CH2Cl2:hexanes) to give ether 20a (106 mg, 100%)
as a white solid: Rf 0.30 (1:1 hexanes:CH2Cl2); mp 86-87 °C
(hexanes:CH2Cl2); IR (KBr, thin film) νmax 1600, 1458, 1420,
1365, 1273, 1124, 1078, 751 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.81 (dd, 1H, J ) 0.5, 8.5 Hz), 7.32 (t, 1H, J ) 8.0 Hz), 6.92
(d, 1H, J ) 7.5 Hz), 6.69 (d, 1H, J ) 12.0 Hz), 3.99 (s, 3H),
3.95 (s, 3H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.2
(d, JC-F ) 7.0 Hz), 153.3 (d, JC-F ) 240.5 Hz), 152.0, 135.9 (d,
JC-F ) 13.5 Hz), 125.0, 124.6, 121.4, 114.7, 107.6, 96.6 (d, JC-F
) 27.5 Hz), 62.7, 56.3, 55.9; MS (CI, NH3) m/z 237 (M + H)+,
254 (M + NH4)+; HRMS (CI) m/z calcd for C13H14FO3 (M +
H)+ 237.0927, found (M + H)+ 237.0923. Anal. Calcd for C13H13-
FO3: C, 66.09; H, 5.55. Found: C, 66.14; H 5.45.
FIGURE 3. Proposed carbenium ion intermediates in the
synthesis of naphthols from cycloadducts 11a and 16b.
2-substituted furans 10b and 10c (Table 3) could be
utilized in the second Diels-Alder reaction (Scheme 2,
Figure 2). In general the regioselectivites of the cycload-
dition and rearomatization reactions were low except in
the examples (Table 2, entry 4 and Table 3, entry 4) when
only one anthracenol product was possible.
In conclusion, we have identified a new iterative double
benzyne-furan Diels-Alder precursor 8 that may be
used to generate a range of substituted naphthols and
anthracenols in moderate to high yield. Further aspects
of the chemistry of the double benzyne cyclohexa-1,2,3-
trien-5-yne (1) will be reported in due course.
Experimental Section
7-Fluoro-5,8-dimethoxy-1-naphthol (13a). n-BuLi (2.5 M
in hexanes; 0.46 mL, 1.15 mmol) was added with stirring to
difluoride 8 (200 mg, 1.15 mmol) in dry THF (4 mL) at -78
°C and the reaction mixture was maintained at this temper-
ature for 15 min. After this time, furan (10a) (0.13 mL, 1.73
mmol) was added and the mixture allowed to warm to 0 °C
over 2 h before being quenched with H2O (5 mL), extracted
with Et2O (2 × 15 mL), dried (Na2SO4), rotary evaporated, and
chromatographed (4:1 CH2Cl2:hexanes to 1:0 CH2Cl2:hexanes)
to give the cycloadduct 11a (205 mg, 80%) as a clear oil: Rf
0.28 (CH2Cl2); IR (KBr, thin film) νmax 1631, 1611, 1496, 1436,
1249 cm-1 1H NMR (300 MHz, CDCl3) δ 7.09 (dd, 1H, J )
;
5,9,10-Trimethoxy-1-anthracenol (22a)31 and 8,9,10-
Trimethoxy-1-anthracenol (23a). Cycloadduct 21a (82 mg,
63%), prepared from fluoride 20a and furan 10a as for 11a
and chromatography (1:1 Et2O:hexanes), was obtained as a
yellow oil: Rf 0.21 (1:1 Et2O:hexanes); IR (KBr, thin film) νmax
1648, 1604, 1521, 1448, 1366, 1325, 1264, 1075 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.75 (d, 1H, J ) 8.5 Hz), 7.39 (t, 1H, J )
8.0 Hz), 7.00 (ca. s, 2H), 6.93 (d, 1H, J ) 7.5 Hz), 6.21 (s, 1H),
6.07 (s, 1H), 4.06 (s, 3H), 3.99 (s, 3H), 3.87 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 156.5, 144.7, 144.6, 141.3, 140.9, 134.7,
130.5, 127.6, 126.3, 119.7, 115.6, 107.8, 81.3, 79.6, 63.1, 60.6,
56.3; MS (CI, NH3) m/z 285 (M + H)+; HRMS (CI) m/z calcd
for C17H17O4 (M + H)+, 285.1127, found (M + H)+ 285.1116.
Subsequent aromatization, using hydrochloric acid in THF and
chromatography (3:2 CH2Cl2:hexanes), as for 12a, gave an
inseparable mixture (4:1) of the anthracenols 22a and 23a (67
mg, 82%) as a yellow oil: Rf 0.51 (7:3 CH2Cl2:hexanes); IR
1.5, 5.5 Hz), 7.04 (dd, 1H, J ) 1.5, 5.5 Hz), 6.38 (d, 1H, JH-F
) 13.0 Hz), 5.97 (s, 1H), 5.92 (s, 1H), 3.90 (s, 3H), 3.77 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 153.5 (d, JC-F ) 247.5 Hz), 147.8
(d, JC-F ) 9.0 Hz), 143.4, 142.2, 141.7, 136.7 (d, JC-F ) 14.0
Hz), 130.9, 99.3 (d, JC-F ) 24.0 Hz), 80.8 (d, JC-F ) 2.5 Hz),
80.1, 61.5, 56.3; MS (CI, NH3) m/z 223 (M + H)+; HRMS (CI)
m/z calcd for C12H12FO3 (M + H)+• 223.0771, found (M + H)+
223.0761. Aqueous HCl (6 M, 10 mL) was added with stirring
to the cycloadduct 11a (1.92 g, 8.64 mmol) in MeOH (40 mL)
and the mixture heated at reflux for 3 h. Upon cooling to 20
°C, crystals formed which were filtered off and washed with
cold MeOH, and recrystallized from MeOH to give the naph-
thol 13a (1.66 g, 86%) as pale yellow needles: Rf 0.25 (1:1
hexanes:CH2Cl2); mp 71-72 °C (MeOH); IR (KBr, thin film)
νmax 3313, 1626, 1519, 1445, 1378, 1246, 1169, 1046, 983, 811
(KBr, thin film) νmax 3374, 1414, 1377, 1253, 1121 cm-1 1H
;
(28) Futagami, S.; Ohashi, Y.; Imura, K.; Hosoya, T.; Ohmori, K.;
Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41, 1063.
(29) Matsumoto, T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron
Lett. 1991, 32, 6735.
(31) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. J. Am. Chem.
Soc. 1991, 113, 6982.
(30) Cram, D. J. J. Am. Chem. Soc. 1964, 86, 3767.
3528 J. Org. Chem., Vol. 70, No. 9, 2005

Iterative Double Benzyne-Furan Diels-Alder Reactions
NMR (400 MHz, CDCl3) δ 10.32 (s, 0.2 H), 9.80 (s, 0.8H), 7.91
(dd, 1H, J ) 1.0, 9.0 Hz), 7.76 (dd, 1H, J ) 1.0, 9.0 Hz), 7.37
(m, 2H), 6.91 (dd, 1H, J ) 1.0, 7.5 Hz), 6.78 (d, 1H, J ) 7.5
Hz), 4.09 (s, 2.4H), 4.08 (s, 0.6H), 4.07 (s, 2.4H), 4.06 (s, 0.6H),
4.01 (s, 0.6H), 4.00 (s, 2.4H); 13C NMR (100 MHz, CDCl3) δ
156.5, 155.7, 154.5, 153.1, 149.8, 148.9, 148.6, 147.1, 127.8,
127.2, 127.0, 126.4, 125.9, 125.6, 118.5, 116.6, 115.2, 114.2,
113.9, 113.0, 109.7, 108.8, 108.6, 104.1, 103.8, 64.7, 63.9, 63.3,
62.6, 56.1; MS (CI, NH3) m/z 285 (M + H)+; HRMS (CI) m/z
calcd for C17H17O4 (M + H)+ 285.1127, found (M + H)+
285.1131.
Organic Chemistry in Medical Sciences at Imperial
College, and the Engineering and Physical Sciences
Research Council for generous support of our studies.
We additionally thank Dr. Andrew P. White for X-ray
crystal structure determinations and Peter R. Haycock
and Richard N. Sheppard for high-resolution NMR
spectroscopy.
Supporting Information Available: Additional experi-
mental procedures and structural data for all new compounds;
X-ray crystallographic structures for 13a and 17a; copies of
1H NMR, 13C NMR, and NoESY NMR spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank Glaxo SmithKline for
the generous endowment (to A.G.M.B.), the Royal
Society and the Wolfson Foundation for a Royal Society
Wolfson Research Merit Award (to A.G.M.B.), the Wolf-
son Foundation for establishing the Wolfson Centre for
JO050112E
J. Org. Chem, Vol. 70, No. 9, 2005 3529